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This is a very important paper illustrating for the first time at high resolution the relation between Abeta oligomers and the condition of dendritic spines in a highly significant animal model of AD. Obviously, several points remain to be addressed, for instance the presence of AMPA and NMDA receptors in the neurite membranes immediately surrounded by the oligomers (they could reveal a distribution similar to that imaged for the dendritic spines with respect to Abeta oligomer gradient) and the levels of free calcium in neurons contacted by Abeta oligomers. However I trust that, when provided, those results will confirm the direct effect of Abeta oligomers on the neuritic membrane.

Another point that must still be clarified is the following: if Abeta oligomers leak from mature fibrils found in the plaques, why in many cases do people bearing plaques not suffer the symptoms of AD? I think that a possible explanation can be searched in several recent papers indicating that Abeta and other proteins can polymerize into fibrils with different structural features, and hence stabilities, depending on several factors including environmental conditions. It could well be that those plaque-bearing people who do not suffer AD have highly stable Abeta fibrils that actively and unidirectionally recruit Abeta monomers and oligomers before they can damage neurons. It would be interesting if the authors check for the presence of Abeta oligomers around the plaques in samples from plaque-bearing asymptomatic people.

The paper by Koffie et al., by showing correlation between oligomeric Aβ and PSD loss, adds significantly to our appreciation of mechanisms by which flavors of APP, especially of Aβ, attack synapses in Alzheimer disease. There are now publications that demonstrate Aβ induced decrements not only of postsynaptic sites (Koffie, et al., 2009; Lacor et al., 2004) but also of presynaptic entities (e.g., Kelly, et al., 2005; Yao et al., 2003; Callahan et al., 1999). But what is the contribution of synaptic deficits to the cognitive declines of AD? The early studies of DeKosky and Scheff (1990) and Terry et al. (1991) agree in finding a correlation of about 0.70 between postmortem measures of synapse density and antemortem scores on cognitive tests. However, a correlation of 0.7 yields an R2 of about 0.50 which leaves 50 percent of the variance in cognitive scores unaccounted for by synapse density. Where might the missing 50 percent lie? Of course, it is presumptuous to assert that synapse density in one small tissue block from a single brain region should explain a phenomenon as complex as cognition. However, let us proceed. May part of the missing 50 percent be attributed to the fact that reduced synapse density in a shrinking cortex means an even greater loss of synapses than that indicated by density data alone? May part of the missing 50 percent be attributed to data indicating that even synapses that are structurally present may not be optimally functional—as evidenced by data showing reduced expression of dynamin 1 in AD (Kelly et al., 2005; Yao et al. 2003), by reduced expression of synaptophysin by single neurons in association with tau phosphorylation or tangles (Callahan et al., 1999), as well as by reductions in transmitter systems (e.g., Lanari et al., 2006 for recent, brief review)? And, to what extent might decrements in these indices of synaptic functional capacity be a consequence of or a cause of synaptic loss?

Synapses are unquestionably central players in the pathophysiology of AD, and we are starting to understand how various flavors of Aβ, as well as other molecules, act on synapses in AD. But it is clear that there are also other important players. How they relate to each other, which are drivers and which are driven; where they all fit into the pathophysiological cascade of Alzheimer’s disease remains to be established.

This article by Koffie et al. contributes importantly to elucidating the contribution of amyloid plaque pathology to synapse loss in Alzheimer’s disease. Heretofore, studies examining the effects of Aβ on synapse morphology have been performed primarily in ex vivo paradigms; however, this work sheds light on spine dynamics at the plaque interface in vivo.

Decreased synapse density has been well documented in human brain affected by AD (1). Importantly, the extent of synapse loss correlates with the severity of dementia, a finding also applicable to individuals with mild cognitive impairment (2, 3). Aβ is most commonly implicated as the pathogenic species responsible for the initial insidious loss of synapse density (4-6). While biochemical and genetic evidence suggests that accumulation of parenchymal Aβ is a critical initiator, a finding requiring reconciliation is that amyloid plaque burden does not correlate strongly with the severity of disease (7,8). Soluble Aβ, on the other hand, correlates strongly with disease severity, and specifically oligomeric assembly forms are the ones to demonstrate robust effects on synapse physiology. It is within this context that Koffie et al. examines how Aβ oligomers loosely associated at the periphery of neuritic plaques affects synapse density. While prior work by Spires-Jones et al. (9) demonstrated that synapse loss was most pronounced within 30 μm of plaques, the identity of the toxic species contained within this complex β-sheet rich structure remained unidentified. By using array tomography and an antibody characterized as Aβ oligomer-specific (10), the authors here present compelling evidence that implicates oligomeric Aβ surrounding insoluble plaques as the likely culprit inducing synapse loss.

The authors first demonstrate using in vivo multiphoton imaging and postmortem sectioning that the vast majority of compact plaques contain a penumbra that is positive for Aβ oligomers as judged by NAB61 immunostaining. Array tomography is subsequently used to illustrate that synapse density is reduced within the compact portion of plaques as well as in the oligomer-rich halo region. The magnitude of synapse loss is blunted with increasing distance, with this significant difference extending up to 20 μm radially from the halo margins. The authors also describe that the NAB61 signal co-localizes with PSD-95 puncta, suggesting an interaction of Aβ oligomers with post-synaptic components. Of physiologic relevance, spines associated with Aβ oligomers were smaller, suggestive of a morphologic manifestation of synapse depression. Taken together, these findings are all highly suggestive that soluble Aβ oligomers are enriched at amyloid plaques and can ultimately initiate the synapse loss observed in AD brain.

This powerful combination of in vivo multiphoton imaging, postmortem analysis with array tomography, and Aβ oligomer-specific reagents opens up a new avenue for understanding AD pathophysiology. With these tools in hand and other ones now emerging, the field is now poised to visualize answers that have been elusive in the past. For instance, it may be of interest to address whether spine density is similarly affected in regions surrounding diffuse plaques that are concentrated in Aβ oligomers. Given that compact plaques contain a panoply of non-Aβ factors, the relatively more simple composition of diffuse plaques may be able to provide additional direct evidence that Aβ oligomers are sufficient to induce synapse loss. Second, is this synapse loss reversible? Given the recent clinical trials examining the therapeutic advantage of passive immunization, NAB61 (or other oligomer-specific antibodies) may provide insight as to whether clearance of soluble higher order Aβ assembly forms can prevent or reverse the dramatic spine loss surrounding amyloid plaques. Third, application of more recently developed higher resolution imaging techniques, such as stimulation emission depletion (STED) microscopy, may provide clearer visualization of the more subtle changes in synapse structure that take place near plaques as described in this study or elsewhere in the parenchyma. Lastly, the authors suggest a physiologic role for Aβ oligomers in regulating synapse function. A cross of APP transgenic mice with channel rhodopsin-2 (ChR2), halorhodopsin (NpHR) mice (11) may be useful to further examine the general role of network dysfunction (12,13) in Aβ oligomer rich parenchyma, such as the penumbra surrounding compact plaques described by Koffie et al. More specifically, by expressing these optically activated ChR2/NpHR ion channels, neuronal activity can be focally modulated revealing perturbations in the circuitry surrounding amyloid plaques.

This paper confirms, in vivo, a role for soluble Aβ oligomers in the disassembly of synapses surrounding plaques. The authors for the first time apply array tomography to quantitatively assess the interaction between postsynaptic densities/spines with microdeposits of oligomeric Aβ present in a halo extending from the edge of the dense core of plaques. Interestingly, they find that the reduction in the density but not in the size of postsynaptic densities is inversely correlated to the distance from the plaques. Overall, this paper suggests that in vivo plaques act as a source of toxic soluble oligomeric Aβ, which directly interacts with dendritic spines, causing their disappearance. However, these data don’t explain why 60 percent of postsynaptic densities and dendritic spines resist the toxic effects of Aβ, or why plaques in elderly individuals are not always associated with cognitive decline. Maybe the answer for the latter point can be found in a recent paper (Lesne et al., 2008) where the authors studied plaque-bearing mice with reduced levels of oligomeric Aβ assemblies and find that they have intact memory function. Finally Koffie et al. describe oligomeric Aβ puncta either juxtaposed to PSD clusters or on the extracellular surface of dendritic spines (see Fig. 4C) and occasionally of presynaptic compartments. However, due to limitation in their technique they cannot exclude the possibility that the Aβ puncta, even though they appear on the extracellular surface of dendritic spines, could be in reality on or within the glia processes surrounding individual synapses.

Several papers in 2009 have explored the physiological consequences of Aβ oligomers in Alzheimer disease. In this study from Brad Hyman’s lab, a novel method enabling precise quantification of small structures was adopted to study the presence of Aβ oligomers in Alzheimer brains. The technique, based on immunofluorescence on ultrathin tissue sections, is called array tomography. The lab group found that oligomeric Aβ is deposited as a halo around senile plaques in the Alzheimer brain, but that virtually no oligomers could be found more distant than 50 μm from the plaques. In a second part of this work, transgenic mouse brains were analyzed. Here, micro-deposits of oligomeric Aβ were found to be associated with a subset of excitatory synapses. Interestingly, those synapses were considerably smaller than synapses not in contact with oligomeric Aβ. This work adds to our knowledge about both the relationship between plaques/oligomers and about the pathogenic role of Aβ oligomers in the affected brain.